PCLO encodes piccolo, a scaffold protein of the presynaptic active zone (CAZ) that organizes the structural and functional architecture of synapses. Piccolo participates in forming Piccolo-Bassoon transport vesicles (PTVs) that deliver presynaptic components along axons, and at mature synapses regulates spatial organization of synaptic vesicle clusters and the readily releasable pool 1. Beyond structural roles, PCLO functions in presynaptic protein ubiquitination through SIAH1 interaction, presynaptic autophagy regulation, and synapse-to-nucleus signaling via CTBP1 association, linking synaptic activity to gene expression changes. PCLO variants are implicated in multiple psychiatric disorders: genome-wide association studies identified PCLO among synaptic structure genes contributing to post-traumatic stress disorder risk 2, and SNP rs2522833 showed significant association with depressive disorders in meta-analysis 3. Expression and genetic variation studies implicate PCLO in bipolar disorder, with intronic SNP rs13438494 significantly associated with disease 4. Recent whole-exome sequencing identified PCLO as a schizophrenia risk gene carrying damaging rare variants 5, with this association conserved across diverse ancestral populations 6. These findings establish PCLO as a synaptic organizer with pleiotropic contributions to psychiatric disease susceptibility, though effect sizes remain modest.